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Combination cancer therapies

Pending Publication Date: 2022-02-17
THE BOARD OF RGT UNIV OF OKLAHOMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention was made with government support and has certain rights. The technical effects of the invention are not fully understood, but it can be inferred that it was developed to address a certain problem or invention related to cancer research with the aim of improving diagnosis, treatment, or prevention of cancer.

Problems solved by technology

Both of these therapies have significant side effects that limit dosing and duration of treatment.
Furthermore, olaparib caused an increased risk of developing secondary cancers.

Method used

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  • Combination cancer therapies
  • Combination cancer therapies
  • Combination cancer therapies

Examples

Experimental program
Comparison scheme
Effect test

example 1

SHetA2—PRIMA-1 / PRIMA-1MET Drug Combinations

Methods

[0149]Cell Lines, Plasmids and Drugs

[0150]Ovarian cancer cells lines A2780 (RRID:CVCL_0134), OV-90 (RRID:CVCL_3768), SKOV3 (RRID:CVCL_0532), COV362 (RRID:CVCL_2420), OVSAHO (RRID:CVCL_3114), Caov3 (RRID:CVCL_0201), and OVCAR4 (RRID:CVCL_1627) (all from American Type Culture Collection / ATCC Manassas, Va., USA) were cultured in RPMI1640 medium containing 10% FBS and 1×antibiotic / antimycotic. The MESOV / GFP-luc (RRID:CVCL_CZ92) cell line (gift from Dr. Francois Moisan, Stanford University) (MESOV) was cultured in DMEM-high glucose medium with 10% FBS. SKOV3 cells stably transfected with mutant p53 (R248W, R273H) or parent vector were provided by Jeremy Chien, PhD (University of Kansas Medical Center). Human fallopian tube secretory epithelial cells (hFTSECs) were isolated from fallopian tube fimbriae surgical specimens under an IRB approved protocol. All cell lines were authenticated by autosomal short tandem repeat (STR) profiles determ...

example 2

SHetA2—Palbociclib Drug Combination

[0198]CDK 4 / 6 inhibitors (e.g., Palbociclib, Ribociclib and Abemaciclib) are structurally-related drugs currently FDA approved for treatment of cancer. As a demonstration that SHetA2 works synergistically with the CDK 4 / 6 group of drugs, SHetA2 was tested for its ability to interact synergistically with palbociclib.

[0199]Palbociclib, an FDA approved anticancer drug for treatment of breast cancer, was evaluated in combination with SHetA2 because they inhibit cyclin D1 / CDK4 / 6 complex-driven cancer cell growth through complementary mechanisms. Palbociclib binds and inhibits the CDK4 / 6 kinase activity. SHetA2 disrupts mortalin complexes and mortalin is known to bind cyclin D1. Another SHetA2 binding target, Hsc70, stabilizes the cyclin D1 / CDK4 / 6 complex. Furthermore, SHetA2 causes degradation of cyclin Dl in cell lines, and in animal models in association with tumor reduction.

[0200]Strong synergy was observed between SHetA2 and Palbociclib when used to...

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Abstract

Drug combinations of a heteroarotinoid (e.g., SHetA2), and an Azabicyclooctan-3-one derivative (e.g., PRIMA-1 or PRIMAMET) and / or, a CDK4 / 6 inhibitor (e.g., Palbociclib, Abemaciclib, or Ribociclib), which are synergistically-effective as anti-cancer treatments, and kits and methods of use of such drug combinations.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority under 35 U.S.C. § 119(e) to U.S. Ser. No. 62 / 730,345, filed Sep. 12, 2018, the entirety of which is hereby expressly incorporated by reference herein.GOVERNMENT SUPPORT[0002]This invention was made with government support under U.S. National Cancer Institute grants RO1 CA196200 and RO1 CA200126. The government has certain rights in the invention.BACKGROUND[0003]Despite being cancer free after primary cytoreductive surgery and platinum-based chemotherapy, approximately 70% of ovarian cancer patients will relapse after 3 years. Maintenance therapy using the FDA-approved PARP-1 inhibitor, olaparib, in BRCA mutation positive patients, or the angiogenesis inhibitor, bevacizumab, in all other patients, has been shown to prolong time to recurrence, however no improvement in overall survival was found in long term follow-up for bevacizumab or interim analysis of 21% data for olaparib. Both of these therapie...

Claims

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Application Information

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IPC IPC(8): A61K31/382A61K31/439A61K31/519A61K31/506A61P35/00
CPCA61K31/382A61K31/439A61P35/00A61K31/506A61K31/519A61K45/06A61K2300/00
Inventor BENBROOK, DORIS MANGIARACINARAMRAJ, SATISH KUMAR
Owner THE BOARD OF RGT UNIV OF OKLAHOMA
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